GB1587378A - Antitussic or anti-thrombotic pharmaceutical compositions and their preparation - Google Patents
Antitussic or anti-thrombotic pharmaceutical compositions and their preparation Download PDFInfo
- Publication number
- GB1587378A GB1587378A GB14623/78A GB1462378A GB1587378A GB 1587378 A GB1587378 A GB 1587378A GB 14623/78 A GB14623/78 A GB 14623/78A GB 1462378 A GB1462378 A GB 1462378A GB 1587378 A GB1587378 A GB 1587378A
- Authority
- GB
- United Kingdom
- Prior art keywords
- glaucine
- composition according
- active agent
- hydrobromide
- physiologically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
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- 239000000203 mixture Substances 0.000 claims description 62
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- 239000000243 solution Substances 0.000 claims description 37
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- 239000012528 membrane Substances 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
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- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 235000006502 papoula Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
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- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
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- 239000004926 polymethyl methacrylate Substances 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical class [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 1
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- 238000010583 slow cooling Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- NKAAEMMYHLFEFN-ZVGUSBNCSA-M sodium;(2r,3r)-2,3,4-trihydroxy-4-oxobutanoate Chemical compound [Na+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O NKAAEMMYHLFEFN-ZVGUSBNCSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000003033 spasmogenic effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
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- MQAYPFVXSPHGJM-UHFFFAOYSA-M trimethyl(phenyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)C1=CC=CC=C1 MQAYPFVXSPHGJM-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Description
(54) ANTI-TUSSIC OR ANTI-THROMBOTIC
PHARMACEUTICAL COMPOSITIONS AND THEIR
PREPARATION
(71) We KARL O. HELM Aktiengesellschaft, of Nordkanalstrasse 28, 2000 Hamburg, 1, Federal Republic of Germany, do hereby declare the invention, for which I pray that a patent may be granted to me, and the method by which it is to be performed, to be particularly described in and by the following statement:
This invention relates to pharmaceutical compositions having anti-thrombotic (thrombozyte aggregation inhibiting) or anti-tussic effects, and to methods of preparing such compositions.
It is known that papaverine has an anti-thrombotic effect, but in effective concentration has such strong side effects that it is in practice not suitable for this purpose.
A medical suppression of the cough reflex occurring in bronchial and pulmonary illnesses for freeing the breathing tract from mechanical or pathological irritations is desirable when a dry, irritated cough occurs, as it does for example in asthma, whooping cough, tuberculosis and lung cancer. The best known coughinhibiting substance is codeine which acts on the cough centre, but when given orally has a slight addictive effect because de-methylation in the organism produces morphine. This effect is even more pronounced when codeine is injected.
The most important side effects in codeine therapy are constipation and depression of the breathing action, and for this reason the use of codeine is in many cases contra-indicated or at least entails disadvantages. A further objection to codeine is that its manufacture requires the cultivation of opium poppies.
It is also known that the alkaloid d-glaucine which is isolated from the flowers of the yellow poppy, can be used in cough therapy.
The poppy does not contain l-glaucine, but at least four other alkaloids, whose separation from d-glaucine is extremely difficult. The d,l-glaucine synthesized, starting from papaverine, by oxidative ring-closing reaction of laudanosoline ("Angewandte Chemie" 1967, pages 815 and 816) contains considerable quantities of an hitherto not recognised by-product, which crystallizes together with the glaucine salt. This by-product has been found to be l-(N,N-dimethylaminoethyl)3,4,6,7-tetramethoxyphenanthrene, which is apparently produced by Hofmann degradation. In view of the phenanthrene structure and the often sympathomimetically active diemthylaminoethyl group of this compound, glaucine contaminated with such a by-product cannot be used in pharmaceutical products.
The pharmaceutical compositions of the present invention have antithrombotic (thrombozyte aggregation inhibiting) or anti-tussic effects which are therapeutically active at a low concentration of the active compound and are largely free from undesired side effects.
The anti-tussic compositions when given orally, have an improved long-lasting central cough-inhibiting effect, are not addictive and largely free from the undesired gastrointestinal side effects of the known products.
The invention provides a pharmaceutical composition comprising a physiologically acceptable solid or aqueous liquid carrier and at least one therapeutically active agent which is an aporphine derivative selected from l,2,9,10-tetrahydroxyaporphine (hereinafter referred to as tetrahydroxyaporphine), and glaucine containing l-glaucine; or physiologically acceptable salts or quaternary N-alkyl-ammonium derivatives thereof.
Examples of salts of such active agents are a halogen acid salt, a tartrate, an Nmethoxyhalogenide, and embonate.
Even at active substance concentrations far below what is necessary for papaverine, the pharmaceutical compositions according to the invention have pronounced anti-thrombotic effect and are largely free from the side effects which occur when papaverine is used.
Preferably the said active agent is glaucine of which 50% to 100% is l-glaucine, or its physiologically acceptable salt or N-methohalogenide. A further preferred composition according to the invention is one in which the glaucine is d, l-glaucine, or a derivative thereof as hereinbefore set forth.
Thus when the said active agent is glaucine, the glaucine preferably consists of from 50% to 100% by weight l-glaucine, and may be d,l-glaucine.
To achieve an anti-thrombotic (thrombozyte aggregation inhibiting) effect, the compositions of the present invention may be in dosage unit form comprising an aqueous liquid or solid carrier and from 100 to 800 mg, preferably from 100 to 500 mg of active agent per dosage unit. Thus the said composition may be in the form of a pill, dragee, tablet or capsule. Alternatively such compositions may be adapted for injection, and comprise a solution or the active agent in a physiologically acceptable aqueous liquid carrier.
To achieve an anti-tussic effect, the compositions of the present invention may be in dosage form adapted for oral administration, comprising an aqueous liquid or solid carrier and from 1 to 1000 mg of active agent per dosage unit. Thus the composition may be in the form of a pill, dragee, tablet or capsule, containing for examle from 5 to 50 mg of active agent per dosage unit, or may be in the form of a syrup containing for example from 1 to 10 rng of the active agent per ml.
Such compositions provide improved effects. Thus when compared with previously used anti-tussic compositions containing codeine they are substantially free of spasm-inducing side effects in the intestinal region, and when compared with compositions containing d-glaucine as the active agent, I-glaucine, or combinations of d-glaucine and l-glaucine, e.g. d,l-glaucine, or derivatives thereof as herein before referred to, provide an improved effect.
Pharmaceutical compositions according to the invention preferably contain glaucine embonate or glaucine tartrate. Glaucine embonate provide a considerably prolonged anti-cough effect, without delaying the onset of said effect.
The invention also provides compositions comprising glaucine, a glaucine salts or N-methohalogenides, free from l-(N,N-dimethylaminoethyl)-3,4,6,7-tetra- methoxyphenanthrene.
The invention also provides a method of preparing a pharmaceutical composition for administration to humans to obtain an anti-tussic or a thrombozyte aggregation inhibiting effect, comprising formulating a mixture or solution of a physiologically acceptable solid or aqueous liquid carrier with at least one active agent selected from glaucine containing l-glaucine, or its physiologically acceptable salt or quaternary N-alkyl ammonium derivative.
The invention is hereinafter particularly described and illustrated by the following Examples and Comparative Tests.
Preparation of Tetrakvdroxyaporphine Hydrochloride
For making laudanosine there was added to 225 g (0.6 Mol) of papaverine hydrochloride in 2 litres of 50% aqueous methyl alcohol a solution of 30 g sodium hydroxide in 300 ml water, the addition being made slowly. The resulting precipitate was filtered off and dried for 20 hours at 60"C. The product was 201 g of papaverine base with a melting point of 144 to 1460C (yield 98%).
200 g (0.6 Mol) of the papaverine base was dissolved in 200 ml of methyl alcohol. To the solution there was added 120 ml of methyl iodide and the whole heated to boiling during 6 hours. After cooling, the crystalline product was filtered off and dried. The product was 280 g of papaverine methiodide with a metling point of 127 to 1290C (yield 97%).
200 g (0.4 Mol) of the papaverine methiodide was suspended in 2 litres of a 10"ó aqueous methyl alcohol and to this mixture there was added sodium borohydride until complete solution was obtained and the yellow-orange colouration has disappeared. The resulting solution was poured into 12 litres of water and the resulting white precipitate was filtered off and dried. The product was 230 g of laudanosine with a melting point of 113 to 1 150C (yield 78%).
To make laudanosoline hydrobromide 121 g (0.34 Mol) of laudanosine was heated in 600 ml of 40% hydrobromic acid for about 10 hours, until all the methyl bromide was removed. After cooling, the solution, the crystalline product was separated. The product was 100 g of laudanosoline hydrobromide with a melting point of 230"C (yield 77%).
To make tetrahydroxyaporphine hydrochloride, 98 g (0.26 Mol) of laudanosoline hydrobromide was dissolved in 1.2 litres of a 50% aqueous methyl alcohol at 800 C. After complete solution, the solution was cooled down to 60C by adding ice, after which there was added a filtered solution, which had also been cooled to 60C, of 100 g (0.62 Mol) of iron (III) chloride in 500 ml of 50% aqueous methyl alcohol. After one minute there was added 1.5 litres of concentrated hydrochloric acid and the solution was allowed to stand at room temperature. The precipitated grey-brown crystals were filtered off, washed with acetone and dried.
The product was 43 g of tetrahydroxyaporphine hydrochloride showing a melting point of 242 to 2440C (yield 50%).
Preparation of d,l-Glaucine Hydrobromide
For making d,l-glaucine hydrobromide, 6 g (0.018 Mol) of tetrahydroxyaporphine hydrochloride was dissolved with warming in 850 ml of methyl alcohol.
In a separate operation, 21.6 g (0.126 Mol) of trimethylphenylammonium chloride in methyl alcohol was reacted with a solution of 8.5 g (0.15 Mol) of KOH in methyl alcohol. After filtering off the precipitated potassium chloride, the filtrate was made up to 840 ml with methyl alcohol. The two solutions were then mixed together slowly under a protective gas and added slowly over 6 hours to anisol which had been heated to 1100 C, the methyl alcohol distilling off. After completion of the addition the solution was cooled and a black, amorphous residue was removed by filtering. The resulting dark green filtrate was evaporated under vacuum until dry. To the residue there was added 5 ml of ehtanol, 15 mls of hydrobromic acid and 20 mls of ethyl acetate. From the resulting mixture a product crystallized out and was filtered off and dried. The product was 5.5 g of d,l-glaucine hydrobromide with a melting point of 235"C (with decomposition) (yield 67%).
Purification and Resolution of d,l-glaucine.
A thin-layer chromatograph showed that the d,l-glaucine hydrobromide made by the above process contained about 10% of l-(N,N-dimethylaminoethyl)-3,4,6,7tetramethoxyphenanthrene. 60 g of this d,l-glaucine hydrobromide was dissolved in 200 ml of 50% aqeuous ethanol and reacted with an excess of 8.5 g of potassium hydroxide in 50 ml of water.
The resulting mixture was shaken with about 500 ml of chloroform to extract the free d,l-glaucine base. The separated organic phase was dried over anhydrous sodium sulphate and filtered. After evaporating off the solvent 50 g of an oily residue was obtained and this was recrystallized from 75 ml of ethyl acetate. After filtering and drying there was obtained 30.4 g of d,l-glaucine base showing a melting point of 128 to 1300C. After repeated recrystallization from further 100 ml portions of ethyl acetate, there was obtained 25.15 g of d,l-glaucine base with a melting point of 138 to 140"C. By making athin-layer chromatograph it was determined that this contained less than 0.1% of impurities.
After recrystallizing the combined residues from ethyl alochol there was obtained about 5 g of l-(N,N-dimethylaminoethyl)-3,4,6,7-tetramethoxy- phenanthrene with a melting point of 248 to 2500C and a molecular weight, determined by mass spectrometry, of 369.
NMR spectrum: 9.1 3(s,l), 7.88(d,1), 7.66(d,1), 7.46(s,2),
3.97(s,3), 3.93(s,6), 3.86(s,3), 3.44-3.1 4(m,4), 2.73(s,3), 2.52(s,3).
To separate the isomers, 5.09 g (0.014 Mol) of d,1-glaucine was dissolved in 70 ml of ethyl alcohol and the solution reacted with a solution of 2.2 g (0.014 Mol) of d-tartaric acid in 70 ml of ethyl alcohol (500 C). Slow cooling resulted in a fine crystalline precipitate which was filtered off, washed with ether and dried. The product was 3.6 g of l-glaucine-d-bitartrate with a melting point of 210 to 212"C and a specific rotation in water of 26" (yield 93%).
The sill impure l-glaucine-d-bitartrate was reacted with an aqueous solution of sodium hydroxide and extracted with ether. After evaporating the solvent, the residue was dissolved in 50 ml of ethyl alcohol and reacted with a solution of 1.15 g of d-tartaric acid in 50 ml of ethyl alcohol. After separation there was obtained 3.39 g of l-glaucine-d-bitartrate showing a melting point of 212 to 2150C and a specific rotation in water of --32". The specific rotation of the l-glaucine base in ethyl alcohol was -101" (94% optical purity).
2.48 g of l-glaucine was reacted in 15 ml of ethyl alcohol with a small excess of 48% hydrobromic acid. After separation there was obtained 2.78 g of l-glaucine hydrobromide with a melting point of 235"C (with deomposition) (yield 98.5%).
From the mother liquors of the first and second d-bitartrate crystallization there was obtained, after evaporation, a greenish residue, which was dissolved in 20 ml of water, treated with aqueous sodium hydroxide and then extracted with 250 ml of ether. After drying and filtering, the solvent was evaporated, giving 1.67 g of dglaucine with a melting point of 1209C. The specific rotation in alcohol was 104.6 .
By reacting this product with hydrobromic acid there was obtained a d-glaucine hydrobromide with a melting point of 235"C (with decomposition). The d-glaucine obtained my methylation from d-boldine showed a specific rotation in ethyl alcohol of +115 .
Preparation of l-Glaucine Hydrochloride To make l-glaucine hydrochloride, a quantity of l-glaucine was dissolved in a little methyl alcohol and to the solution there was added a small excess of concentrated hydrochloric acid. To the resulting voluminous precipitate there was added ethyl acetate, giving whitish to pink crystals. After filtering, washing with acetone and drying there were obtained white to pink fine crystals of l-glaucine hydrochloride with a melting point of 232 to 2330C.
Preparation of I-Glaucine Hydroiodide
For making l-glaucine hydroiodide, a quantity of l-glaucine was dissolved in 2 n hydrochloric acid and the solution reacted with saturated potassium iodide solution. The resulting crystalline precipitate was recrystallized from a mixture of methyl alcohol and ether. This gave a crystalline, yellowish glaucine hydroiodide with a melting point of 238"C.
Preparation of d-Glaucine Methiodide
A mixture of 3.92 g (0.01 Mol) of glaucine, 1.5 g (0.01 Mol) of potassium carbonate and 5 ml of methyl iodide was heated for 6 hours in methanol. The still hot solution was filtered and the solvent removed under vacuum, giving 4.2 g of dglaucine methiodide with a melting point of 218 to 2200C (yield 85%).
Preparation of Tetrahydrotyaporphine Methochloride
45 g (0.126 Mol) of laudanosine was dissolved in methanol and heated with 15 ml of methyl iodide for 2 hours under reflux. The resulting solid residue was filtered, washed and dried, giving 56 g of laudanosine methiodide monohydrate with a melting point of 238 to 2400C.
30 g of laudanosine methiodide hydrate was dissolved in 150 ml of 48% hydrobromic acid and heated under reflux for 15 hours. The resulting, yellow precipitate was filtered and dried, giving 22.1 g of laudanosoline methobromide with a melting point of 237 to 239"C.
50 g (0.0125 Mol) of laudanosoline methabromide was dissolved in 500 ml of water at 200C and reacted with a filtered aqueous solution containing 40.5 g of iron (Ill) chloride in 500 ml of water. After 24 hours there was added to the dark violet solution 500 ml of concentrated HCI. The mixture was evaporated down to about half its original volume. After adding methanol a yellow precipitate crystallized out. The product was 27.6 g of tetrahydroxyaporphine methachloride with a melting point of 236 to 2390C (yield 63%).
The resulting product, and also the previously obtained products, were identified by ultra-violet, infra-red and NMR spectra and by their melting points.
Preparation of l-Glaucine Embonate For making l-glaucine embonate, 841 mg of l-glaucine was reacted in 10 ml of dimethyl formamide with 459 mg of embonic acid. After heating to complete solution, the mixture was poured into 100 ml of water and the precipitated product filtered and dried. The product was 1.32 g of powdery, slightly brownish l-glaucine embonate with a melting point of 189 to 1920C (yield 100%).
Preparation of d,l-Glaucine Emborate
For making d,l-glaucine embonate, a mixture of 1.42 g of d,l-glaucine and 0.78 g of embinic acid was dissolved in 20 ml of dimethyl formamide and the resulting brown solution was introduced into 400 ml of water. The resulting slightly brownish precipitate was filtered off, washed with water and dried. The product was 1.75 g of d,l-glaucine embonate with a melting point of 188 to 1900C (yield 80%).
Analysis: C85H66N2O14 calculated: C7l.02% H6.05% N 2.55% found: C 69.36% H 5.98% N 2.52%
Preparation of d,l-Glaucine, d,l-Tartrate
For making d,l-glaucine tartrate, 355 mg (1 Mol) of d,l-glaucine in 10 ml of ethyl alcohol was reacted with 150 mg of d,l-tartaric acid in 10 ml of ethyl alcohol at 50"C. After cooling the solution there was obtained 220 mg of optically inactive d,lglaucine-d,l-tartrate with a melting point of 215"C (yield 97%).
Example 1.
Coated pills with an anti-cough effect were made of the following components:
Core: I-glaueine hydrobromide 20 mg
lactose 60 mg
starch 40 mg
talcum 10 mg 130 mg
Coating: gum arabic 4.5 mg
talcum 35 mg
crystallized sugar 80 mg
white wax 0.1 mg
red dye 0.4 mg
120 mg
Example 2.
For making capsules with long-period anti-cough effect, stretch-capsules of hard gelatin were each filled with 160 mg of a mixture of the following components:
d,l-glaucine hydrochloride 10 mg
d,l-glaucine embonate 25 mg
lactose 60 mg
starch 60 mg
magnesium stearate 5 mg
160 mg
Example 3.
For making a syrup with an anti-cough effect the following components were mixed together: I-glaucine hydrobromide 133 mg
saccharose 20 g
sorbitol 45 mg
citric acid 125 mg
p-hydroxybenzoic methyl ester 100 mg
aroma (essence of sweet oranges 1,5 g
distilled water, up to 100 g
Example 4.
For making a medicine intended for injection, ampoules were filled with the following solution:
tetrahydroxyaporphine hydrochloride 11.22 mg
(corresponding to 10 mg of tetrahydroxyaporphine
base)
sodium bisulphite 0.7 mg
tartaric acid 5.01 mg
sodium hydrogen tartrate 10.2 mg
propylene glycol 300 mg
distilled water to 2 ml.
Example 5.
Although the active compounds used according to the invention have an antithrombotic effect already in small dosages, the exact amount of active agent to be used in an anti-thrombotic tablet, dragee or capsule will vary with the severity of the thrombogenic risk of the patient, his weight and his response to the active compound. The active compound shall preferably be compounded with non-toxic edible excipient chemically inert to the active compound. The amount of excipient should preferably be sufficient to separate the particles of the active agent from each other and to cause quick solution or dispersion in the gastric juices in the stomach. To this purpose the composition may comprise 10 to 99%, preferably 20 to 75% of active agent, the rest being carrier material and conventional adjuvants.
Suitable excipients are lactose, sucrose, starch, talcum, stearic acid and its salts, and other commonly used excipients for tabletting and granulation and mixtures thereof.
For preparing anti-thrombotic tablets there were used the following ingredients:
d,l-glaucine hydrobromide 100,0 mg
sucrose 25,9 mg
starch 22,1 mg
acacia 7,8 mg
talc 3,1 mg
magnesium stearate 1,5 mg
stearic acid 1,6 mg
162,0 mg
The active compound was mixed with the sucrose and the gum acacia, and then with the starch made previously into a paste with a small amount of distilled water. This mixture was dried, converted into a granular powder and then blended with the talc, magnesium stearate and the stearic acid which act as mold lubricants.
After mixing in a pony mixer the mixture was tabletted on a conventional tabletting machine.
Example 6.
There were prepared anti-thrombotic capsules each containing:
tetrahydroxyaporphine hydrochloride 400,0 mg
magnesium stearate 4,0 mg
404,0 mg
Example 7.
There were prepared anti-thrombotic tablets each containing:
l-glaucine hydrobromide 200,0 mg
magnesium stearate 2,0 mg
202,0 mg
Example 8.
In a conventional tabletting machine there were prepared anti-thrombotic tablets each containing:
d,l-glaucine hydrobromide 200,0 mg
polyvinylpyrrolidone 15,0 mg
corn starch 20,0 mg
235,0 mg
Alternatively there can be prepared tablets adapted to be subsequently cut, each containing 400 mg active compound.
Example 9.
For making anti-thrombotic capsules hard gelatine capsules were each filled with a mixture of:
d,l-glaucine hydrobromide 200,0 mg
silicagel 10,0 mg
magnesium stearate 2,0 mg
212,0 mg
Comparative test 1.
In order to compare the anti-cough effectiveness of codeine phosphate with the effectivenesses of the different isomers of glaucine hydrobromide, the testing method of Friebel and Reichle was used. 60 guinea pigs with weights between 200 and 300 g were divided up into ten groups of different sizes. Before administering the active substance, each animal was subjected, on the same day as the day of test with the active substance, for a period of 8 minutes to an aerosol of 20% citric acid, the animal being confined in a chamber at constant air pressure. During this control test the number of cough pulses was counted with the help of a pressure transmitter. From these measurements an average control value for each group was calculated. After this preliminary control test, there was administered subcutaneously to each animal of each group a suspension of the active substance in 1% by weight sodium carboxymethyl cellulose. After 30 minutes each animal was again exposed in the test chamber for 8 minutes to the aerosol of 20% by weight citric acid and the number of cough pressure pulses recorded. The different active substances were administered in increasing doses ranging from 3 mg/kg to 100 mg/kg of body weight. Altogether eight different doses wre administered. The results were expressed as percent deviation from the average control value for the group on the same day, the deviation being entered in a diagram against the logarithm of the dose administered. From the resulting effectiveness curve, based on the logarithm of the dose, the coefficient of correlation and the ED50 were calculated for each active substance, by the regression analysis method of Downie and Heath (1965). The values obtained for codeine phosphate, for d-glaucine hydrobromide, for d,l-glaucine hydrobromide and for l-glaucine hydrobromide thirty minutes after administering the active substance are summarized in Table I.
TABLE I
Number of Correlation Rising slope EDso Active substance animals coeff.* of curve mg/kg l codeine phosphate** 41 -0.3956 47.4 20.6 d-glaucine hydrobromide** 59 -0.5340 60.8 54.0 I-glaucine hydrobromide 38 4.6867 -70.96 31.2 d,l-glaucine hydrobromide 25 0.4874 -57.8 27.2 * statistically significant (p < 0.01) for each active substance.
** not according to invention.
These results show that l-glaucine hydrobromide has a considerably lower
effective dose ED50 value compared to d-glaucine hydrobromide, and that
surprisingly the d,l-glaucine hydrobromide has an even lower EDso value than 1
glaucine hydrobromide.
Comparative test 2.
One of the most unpleasant side effect of anti-cough medicine containing codeine is constipation and the occurrence of intestinal spasms. A model test for determining the effects of anti-cough active substances on intestinal motility and on the evacuation action of the stomach-intestinal tract of mice was therefore made. After subcutaneous injection of the active substance, each animal was given, through a throat probe, a 10% by weight suspension of carbon in a 5% by weight aqueous slurry of gum arabic. Two hours later the intestine was sectioned and the length of stomach coecum measured, and also the distance travelled by the carbon expressed as a percent of intestine length. The results are set forth in Table 11.
TABLE II
Distance Standard Dose Number of travelled, deviation Active substance mg/kg animals average % CONTROL 40 74.3 3.6 codeine phosphate** 3 7 70.4 3.5 10 18 74.3 2.4 30 17 34.8* 9.5 100 18 20.6* 4.5 d-glaucine hydrobromide** 10 18 74.6 2.5 30 18 80.1 2.6 100 18 36.4* 4.9 I-glaucine hydrobromide 3 8 74. 3 6.3 10 8 94.3* 2.0 30 8 85.4 4.3 100 8 51.8* 10.6 * significantly different from the control value (p < 0.05).
** not according to invention.
The effects of codeine phosphate, of d-glaucine hydrobromide and of 1
glaucine hydrobromide on intestinal motility were determined at different doses.
For each dose the average value was calculated for a sufficient number of animals.
These results show that l-glaucine hydrobromide, in contrast to d-glaucine
hydrobromide and codeine phosphate, administered in a dose of 10 mg/kg resulted
in a significant increase in intestinal activity. And even when the dose of l-glaucine
hydrobromide is increased to 30 mg/kg and 100 mg/kg, the intestinal motility is
considerably more than the corresponding values for d-glaucine hydrobromide and
codeine phosphate.
Comparative test 3.
Experiments were conducted in vitro tQ determine the effects of different
active substances on the smooth muscles of isolated guinea pig intestine samples
suspended in a bath. After adding to the bath different doses of the active substances, the contractive force of the muscle material was recorded. It was found that codeine at molar concentrations between 1 x 10-5 and 32 x l0-5produces contractions which depend on the dose. d-glaucine showed a dose-dependent increase of spontaneous activity and tone at molar concentrations between I x 10-5 and 8 x 10-5. On the other hand, using l-glaucine at molar concentrations between
1 x 10-5 and 8 x 10-5, a reduction in spontaneous activity and no increase in tone were observed. This shows that l-glaucine, in contrast to d-glaucine and codeine, has no spasmogenic activity.
In further tests it was investigated in what concentrations the active substances being compared suppress spasms induced in isolated guinea pig intestine by carbachol or histamine. it was found that both codeine and d-glaucine are effective against carbachol or histamine at a molar concentration of I x 10-3 or 4 x 10-5. On the other hand d,l-glaucine was effective against histamine at molar concentrations of only 4 x 10-5 to 4 x 10-5 and against carbachol at molar concentrations of only 4 x 10-7.
Comparative test 4.
In å</RT production and electric production of the activity. Using l-glaucine hydrobromide, it was found that at a concentration of 4 x 10-5 the electrically induced spasms are more effectively suppressed, compared to what is obtained using d-glaucine hydrobromide. At a concentration of 8 x 10-5 of l-glaucine hydrobromide the electrically induced contractions are suppressed even more effectively. Using d,lglaucing hydrobromide it was found possible at concentrations of 4 x 10-5 to 6 x 10-5 to suppress the electrically induced spasms practically completely, without at the same time inducing any spontaneous activity. In comparing the values shown in the table it should be observed that when the d,l-glaucine hydrobromide is at the concentration of 4 x 10-5, the d-glaucine hydrobromide and the l-glaucine hydrobromide are each at a molar concentration of 2 x 10-5.
Comparative test 5.
In a series of tests conducted by the method of Domenjoz, the effects of the different active substances on the coughing centre was examined by electrical stimulation of the upper laryngeal nerves of anaesthetized cats. Electrical stimulation of the nerve produces a coughing reflex and the intention is to reduce this by intravenous injection of the active substance. The minimal effective dose
MED is determined by increasing the dose from 0.1 mg/kg of body weight up to 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg and 6.0 mg/kg, until the dose is sufficient for completely suppressing the coughing reflex.
In these tests each animal was given, in the one hand, codein and, on the other hand, at sufficient time intervals also glaucine, so that the ratio of the minimal effective doses of glaucine and codein can be deduced. Table IV shows the minimal effective doses MED and also the observed duration of cough suppression.
TABLE IV
MED Duration, Active substance mg/kg minutes codeine phosphate* 6 18 - 54 d-glaucine hydrobromide* 1 5 - 39 d,!-glaucine hydrobromide 1 44 - 62 * not according to invention.
These results show that both the d-glaucine hydrobromide and the d,l-glaucine hydrobromide completely suppress the coughing reflex already at a dose of I mg/kg of body weight. The dose of codeine phosphate required for this is 6 mg/kg. And it will be observed taht the duration of the effect, at this minimal dose, is considerably greater for the d,l-glaucine hydrobromide than for the d-glaucine hydrobromide.
Comparative test 6.
The equivalent effective doses for codeine phosphate and d,l-glaucine hydrobromide with oral administration were determined on 20 female guinea pigs with body weights between 230 and 600 g. The guinea pigs were divided into four groups. Each animal was then tested as described further above by subjecting the animal for 8 minutes to a 20% citric acid aerosol, the number of cough pulses produced during the 8 minutes being recorded. The average control value obtained in this way for each group of guinea pigs was calculated. After this control test each animal was given, by means of a throat probe in a volume of 10 ml./kg, either doses of 50 or 100 mg/kg of body weight of codeine phosphate, or doses of 100 or 200 mg/kg of d,l-glaucine hydrobromide. One hour after administering the active substance, each animal was once more subjected for 8 minutes to the citric acid aerosol and the number of cough pulses recorded. The results were compared with the control values and expressed as percentages of the control values. The results are shown in Table V.
TABLE V
Cough pulses, Dose percent of Active substance mg/kg control value codeine phosphate* 50 37 100 50 d,l-glaucine hydrobromide 100 30 200 40 * not according to invention.
The results show that a dose of 75 mg of codeine phosphate per kg of body weight has about the same effect as a dose of 150 mg of d,l-glaucine hydrobromide per kg of body weight.
In a further comparative test, 40 female guinea pigs with body weights between 230 and 600 g were divided into 4 groups and each animal was again subjected to the action of a 20% citric acid aerosol for 8 minutes. From the control values thus obtained the average control value for each group was calculated. Each animal of each group was then given, by means of a throat probe, either 75 mg/kg of codeine phosphate, or 135 mg/kg of d,l-glaucine hydrochloride, or 150 mg/kg of d,l-glaucine hydrobromide, or 378 mg/kg of d,l-glaucine embonate. These doses are the equimolar quantities, based on glaucin. After a period of 1, or 3, or 5 or 24 hours each animal was again subjected for 8 minutes to the action of the citric acid aerosol, and the number of cough pulses during this period was recorded. The values thus obtained were compared with the control values and the percent deviation of the average measured value for each group, from the average control value, was calculated. The results are shown in Table VI.
TABLE VI
Cough pulses during 8 minutes, percent of control value, after: Active substance 1 hour 3 hours 5 hours 24 hours codeine phosphate* 1 84 70 84 95 d,l-glaucine hydrobromide 90 47 59 113 d,l-glaucine hydrochloride 80 72 69 102 d,l-glaucine embonate 80 51 57 81 * not according to invention.
These results show that in all the tests the d,l-glaucine salts have a greater
effect than codeine phosphate in reducing the number of cough pulses. In
particular it will be observed that d,l-glaucine embonate has a considerably longer
lasting effect without any delay in the beginning of the effect.
Comparative test 7.
The toxicity thresholds of codeine phosphate, of d-glaucine hydrobromide and of d,l-glaucine hydrobromide were determined in mice by the Wilcox method. It emerged, as shown in Table VII, that d,l-glaucine is considerably less toxic than dglaucine. The toxicities of codeine phosphate and d,l-glaucine hydrobromide are about equal.
TABLE VII
LD50 LD50 peroral subcutaneous Active substance mg /kg mg /kg codeine phosphate* 640 230 d-glaucine hydrobromide * 345 125 d,l-glaucine hydrobromide 686 320 * not according to invention.
Comparative test 8.
The effectiveness of several compounds corresponding to Formula (I) in influencing the aggregation of blood platelets in platelet-rich human blood plasma was compared with the effectiveness of papaverine hydrochloride. For this purpose highly diluted solutions were prepared of the active substances in physiological
NaCI solution, the solutions showing definite molar concentrations. 10 microlitres of each solution was tested, after 5 minutes incubation at 370 C, for its effect on aggregation of the blood platelets under the influence of adenosine diphosphate added to give the critical concentration. The measurements were made by the turpidity method described by Born in "Nature" (1962) on page 927. The critical contentration is the least concentration of adenosine diphosphate which results in primary aggregation of the blood platelets. This is followed by an irreversible secondary aggregation. Table VIII shows the results when compositions according to the invention gave superior results to the known papaverine hydrochloride.
TABLE VIII
Aggregation inhibition at at 5 x 10 molar Compound concentration papaverine hydrochloride * tetrahydroxyaporphorine hydrochloride + tetrahydroxyaporphorine methochloride + d,l-glaucine hydrobromide + l-glaucine hydrobromide + * not according to invention.
Comparative test 9.
The active compounds d,l-glaucine hydrobromide and tetrahydroxyaporphine hydrochloride were selected for in vivo assessment of the anti-thrombotic activity using a modified hamster cheek pouch technique described by Duling, Berne and
Born (1968) and Begent and Born (1970).
Male golden hamsters, weighing 80-120 g, were anaesthetised with intraperitoneal pentobarbitone. The cheek pouch was everted using a cotton bud and spread out over a special Perspex stage. The top layer and connective tissue were removed leaving a thin vascular membrane which was transilluminated from below. The preparation was observed using a Leitz Dialux microscope and long working range objectives at a magnification of x 250. The cheek pouch remained in good condition for the duration of the experiment by continually bathing with
Tyrode solution at a temperature of 37"C.
A micropipette of tip diameter 1--2um was filled with a 0,01 M solution of the sodium salt of adenosine diphosphate in distilled water. The micropipette was manipulated close to a venule of diameter 16--40 um. The reference electrode was placed in contact with the animal. When the negative potential was applied from the external circuit the resultant current of approximately 300 nA ejected adenosine diphosphate (of the order of 2 x 10-14 moles/sec) from the pipette. This caused the formation of a white body (platelet thrombus) at the tip of the pipette or slightly downstream. The growth rate of the thrombus was quantified by noting the time taken for 30%, 50% and 90% of the white body to form. When the current was switched off the white body rapidly embolised and no new white bodies could be formed until the current was reapplied.
In this study the effect of the drug was assessed over a period between 30 and 90 minutes after oral administration of each drug at the dose levels of 2, 5,10 and 20 mg/kg.
The compound was tested at four dose levels in 5 animals each with one group of 5 animals serving as a control. Preparation of the cheek pouch commenced at 15 minutes after dosing and thrombus stimulation commenced at 30 minutes after dosing each animal.
The growth rates were calculated as gradients of the regression lines by a standard programme in a 9100B Hewlett Packard calculator. Dose response curves are obtained by plotting maximum inhibition expressed in percent of control group on thrombus induction in the micro-circulation of the hamster cheek pouch against the dose level. The compounds were shown to inhibit thrombus formation when administered orally. The results are shown in Table IX:
TABLE IX
Oral dose for Maximal Time of maximal maximal maximal inhibition inhibition inhibition Product mg/kg % O/G min (after dosing) glaucine hydrobromide 10 41 60 - 70 tetrahydroxyaporphine 20 29 50 - 60 hydrochloride The dose response curves indicated that the compounds wre active at relatively low dose levels and the inhibitory capacity of each compound tended to plateau at approximately 10 mg/kg.
Comparatile test 10.
In order to investigate the anti-cough effectiveness of orally given codein phosphate, d-glaucine hydrobromide, d,l-glaucine hydrobromide, I-glaucine hydrobromide and l-glaucine-d-tartrate, respectively, guinea pigs were orally dosed with one of the active agents mentioned one hour before being exposed for ten minutes at a 5% citric acid aerosol. In each case the last 5 minutes of the exposure were used for the measurements. The effective doses EDso are shown in Table X:
TABLE X
Oral EDso Compound mgkg Codein phosphate * 94,9 d-glaucine hydrobromide * 198,96 d,l-glaucine hydrobromide 16,0 l-glaucine hydrobromide 7,21 l-glaucine-d-tartrate 6,8 * not according to invention.
WHAT WE CLAIM IS:
1. A pharmaceutical composition comprising a physiologically acceptable so!id or aqueous liquid carrier and at least one therapeutically active agent which is an aporphine derivative selected from tetrahydroxyaporphine, and glaucine containing l-glaucine; or physiologically acceptable salts or quaternary N-alkylammonium derivatives thereof.
2. A composition according to Claim 1, wherein the said active agent is glaucine of which 50% to 100% by weight is l-glaucine, or its physiologically acceptable salt or N-methohalogenide.
3. A composition according to Claim 2, in which the glaucine is d,l-glaucine or its physiologically acceptable salt or N-methohalogenide.
4. A composition according to any of Claims I to 3, in dosage unit form for administration to humans to obtain a thrombozyte aggregation inhibiting effect comprising a liquid or solid carrier and from 100 to 800 mg of the said active agent per dosage unit.
5. A composition according to Claim 4, containing from 100 to 500 mg of the said active agent per dosage unit.
6. A composition according to Claim 4 in the form of a pill, dragee, tablet or capsule.
7. A composition according to Claim 4, for injection and comprising a solution of the said active agent in a physiologically acceptable aqueous liquid.
8. A composition according to any of Claims I to 3, in dosage unit form for oral administration to obtain an anti-tussic effect, comprising a liquid or solid carrier and from I to 1000 mg of said active agent per dosage unit.
9. A composition according to Claim 8 in the form of a pill, dragee, tablet or capsule.
10. A composition according to Claim 9, which contains from 5 to 50 mg of said active agent per dosage unit.
II. A composition according to Claim 8 in the form of a syrup.
12. A composition according to Claim 11, wherein the said syrup contains from
I to 10 mg of the said active agent per ml of syrup.
13. A composition according to any of Claims 1 to 10, comprising glaucine, or glaucine salts of N-methohalogenides, free from l-(N,N-dimethylaminoethyl)3,4,6,7-tetramethoxyphenanthrene.
14. A composition according to any of Claims 1 to 13, comprising glaucine embonate or d,l-glaucine-d,l-tartrate.
15. A composition according to Claim I, substantially as hereinbefore described, with particular reference to the Examples.
16. A method of preparing a pharmaceutical composition for administration to humans to obtain an anti-tussic or a thrombozyte aggregation inhibiting effect, comprising formulating a mixture or solution of a physiologically acceptable solid or aqueous liquid carrier with at least one active agent selected from glaucine containing l-glaucine, or its physiologically acceptable salt or quaternary N-alkyl ammonium derivative.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (19)
1. A pharmaceutical composition comprising a physiologically acceptable so!id or aqueous liquid carrier and at least one therapeutically active agent which is an aporphine derivative selected from tetrahydroxyaporphine, and glaucine containing l-glaucine; or physiologically acceptable salts or quaternary N-alkylammonium derivatives thereof.
2. A composition according to Claim 1, wherein the said active agent is glaucine of which 50% to 100% by weight is l-glaucine, or its physiologically acceptable salt or N-methohalogenide.
3. A composition according to Claim 2, in which the glaucine is d,l-glaucine or its physiologically acceptable salt or N-methohalogenide.
4. A composition according to any of Claims I to 3, in dosage unit form for administration to humans to obtain a thrombozyte aggregation inhibiting effect comprising a liquid or solid carrier and from 100 to 800 mg of the said active agent per dosage unit.
5. A composition according to Claim 4, containing from 100 to 500 mg of the said active agent per dosage unit.
6. A composition according to Claim 4 in the form of a pill, dragee, tablet or capsule.
7. A composition according to Claim 4, for injection and comprising a solution of the said active agent in a physiologically acceptable aqueous liquid.
8. A composition according to any of Claims I to 3, in dosage unit form for oral administration to obtain an anti-tussic effect, comprising a liquid or solid carrier and from I to 1000 mg of said active agent per dosage unit.
9. A composition according to Claim 8 in the form of a pill, dragee, tablet or capsule.
10. A composition according to Claim 9, which contains from 5 to 50 mg of said active agent per dosage unit.
II. A composition according to Claim 8 in the form of a syrup.
12. A composition according to Claim 11, wherein the said syrup contains from
I to 10 mg of the said active agent per ml of syrup.
13. A composition according to any of Claims 1 to 10, comprising glaucine, or glaucine salts of N-methohalogenides, free from l-(N,N-dimethylaminoethyl)3,4,6,7-tetramethoxyphenanthrene.
14. A composition according to any of Claims 1 to 13, comprising glaucine embonate or d,l-glaucine-d,l-tartrate.
15. A composition according to Claim I, substantially as hereinbefore described, with particular reference to the Examples.
16. A method of preparing a pharmaceutical composition for administration to humans to obtain an anti-tussic or a thrombozyte aggregation inhibiting effect, comprising formulating a mixture or solution of a physiologically acceptable solid or aqueous liquid carrier with at least one active agent selected from glaucine containing l-glaucine, or its physiologically acceptable salt or quaternary N-alkyl ammonium derivative.
17. A method according to Claim 16, wherein the said active agent consists of
from 50% to 100% by weight of l-glaucine.
18. A composition according to Claim I which is an anti-thrombotic composition.
19. A composition according to Claim I which is an anti-tussic composition.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2717062A DE2717062C2 (en) | 1977-04-18 | 1977-04-18 | Medicines with an antitussive effect |
DE2717001A DE2717001C2 (en) | 1977-04-18 | 1977-04-18 | Medicines with an antithrombotic effect |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1587378A true GB1587378A (en) | 1981-04-01 |
Family
ID=25771874
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB14623/78A Expired GB1587378A (en) | 1977-04-18 | 1978-04-13 | Antitussic or anti-thrombotic pharmaceutical compositions and their preparation |
Country Status (7)
Country | Link |
---|---|
JP (1) | JPS53130437A (en) |
AU (1) | AU520608B2 (en) |
CA (1) | CA1098035A (en) |
FR (1) | FR2387652A1 (en) |
GB (1) | GB1587378A (en) |
IT (1) | IT1104846B (en) |
NL (1) | NL7803601A (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5645459A (en) * | 1979-09-20 | 1981-04-25 | Otsuka Pharmaceut Co Ltd | Cyclic amine |
FR2843963B1 (en) * | 2002-08-30 | 2004-10-22 | Sederma Sa | NEW NORAPORPHIN-DERIVED MOLECULES |
-
1978
- 1978-04-04 NL NL7803601A patent/NL7803601A/en not_active Application Discontinuation
- 1978-04-13 GB GB14623/78A patent/GB1587378A/en not_active Expired
- 1978-04-17 CA CA301,259A patent/CA1098035A/en not_active Expired
- 1978-04-17 IT IT48932/78A patent/IT1104846B/en active
- 1978-04-17 FR FR7811244A patent/FR2387652A1/en active Granted
- 1978-04-18 JP JP4621578A patent/JPS53130437A/en active Pending
- 1978-04-18 AU AU35198/78A patent/AU520608B2/en not_active Expired
Also Published As
Publication number | Publication date |
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AU3519878A (en) | 1979-10-25 |
IT7848932A0 (en) | 1978-04-17 |
IT1104846B (en) | 1985-10-28 |
NL7803601A (en) | 1978-10-20 |
FR2387652B1 (en) | 1982-04-23 |
JPS53130437A (en) | 1978-11-14 |
CA1098035A (en) | 1981-03-24 |
AU520608B2 (en) | 1982-02-11 |
FR2387652A1 (en) | 1978-11-17 |
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PS | Patent sealed [section 19, patents act 1949] | ||
PCNP | Patent ceased through non-payment of renewal fee |